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Src-mediated phosphorylation of GAPDH regulates its nuclear localization and cellular response to DNA damage

Compared with normal cells, cancer cells develop enhanced DNA damage repair capacity to survive chemotherapy. Emerging evidence has proven that inhibitors of DNA repair pathways are more effective when used in combination with DNA damaging chemotherapeutic drugs. Since the upregulated GAPDH expression has already been discovered in different human cancers, as a new component involved in DNA repair, but the underlying mechanism for the GAPDH response to DNA damage remains unclear. 
Recently, Professor Zhigang Guo’s team published their findings in the online journal of The FASEB Journal (https://faseb.onlinelibrary.wiley.com/doi/full/10.1096/fj.201902904RR).

 

 

We demonstrate that the tyrosine kinase Src can be activated under DNA damage stress and phosphorylate GAPDH at Tyr41. This phosphorylation of GAPDH is essential for its nuclear translocation and DNA repair function. Blocking the nuclear import of GAPDH by suppressing Src signaling or through a GAPDH Tyr41 mutation impairs its response to DNA damage. Nuclear GAPDH is recruited to DNA lesions and associates with DNA polymerase  (Pol ) to function in DNA repair. Nuclear GAPDH promotes Pol  polymerase activity and increases Pol -involved base excision repair (BER) efficiency. Furthermore, GAPDH knockdown dramatically decreases BER efficiency and sensitizes cells to DNA damaging agents. Importantly, the knockdown of GAPDH in colon cancer SW480 cells and xenograft models effectively enhances the sensitivity to the chemotherapeutic drug 5-FU. In summary, our findings provide mechanistic insight into the new function of GAPDH in DNA repair and suggest a potential therapeutic target in chemotherapy.
The first author is Shusheng Ci, the Ph.D student in College of Life Sciences. Associate Professor Feiyan Pan and Professor Zhigang Guo are the co-corresponding authors.